biostudies-literatureGong JNational College Students&apos; Innovation and Entrepreneurship Training ProgramNational College Students' Innovation and Entrepreneurship Training ProgramGuangdong Provincial Science and Technology ProjectsNational Natural Science Foundation of ChinaScience and Technology Projects in GuangzhouPresident Foundation of Nanfang Hospital, Southern Medical University136https://www.ebi.ac.uk/biostudies/studies/S-EPMC12123736biostudies-literatureUnknown13(1)<h4>Background</h4>Sepsis, a critical organ dysfunction resulting from an aberrant host response to infection, remains a leading cause of mortality in ICU patients. Recent evidence suggests that angiotensin-converting enzyme 2 (ACE2) contributes to intestinal barrier function, the mechanism of which is yet to be explored. Additionally, alterations in intestinal microbiota and microbial metabolites could affect gut homeostasis, thus playing a potential role in modulating sepsis progression.<h4>Results</h4>ACE2 shedding weakens the integrity of the intestinal barrier in sepsis. Mice deficient in ACE2 exhibited increased intestinal permeability and higher mortality rates post-operation compared to their wild-type counterparts. Notably, ACE2 deficiency was associated with distinct alterations in gut microbiota composition and reductions in protective metabolites, such as 5-methoxytryptophan (5-MTP). Supplementing septic mice with 5-MTP ameliorated gut leak through enhanced epithelial cell proliferation and repair. The PI3K-AKT-WEE1 signaling pathway was identified as a key mediator of the beneficial effects of 5-MTP administration.<h4>Conclusion</h4>ACE2 plays a protective role in maintaining intestinal barrier function during sepsis, potentially through modulation of the gut microbiota and the production of key metabolite 5-MTP. Our study enriched the mechanisms by which ACE2 regulates gut homeostasis and shed light on further applications. Video Abstract.MicrobiomeACE2 shedding exacerbates sepsis-induced gut leak via loss of microbial metabolite 5-methoxytryptophan.PMC1212373620231212100682170641 and 818735832021A15150125952022010202062023A041Xu QCui WMa YQuan LMeng YLou ALiu XLi XLi YQu PLu HChen ZGong JSong WfalseACE2 shedding exacerbates sepsis-induced gut leak via loss of microbial metabolite 5-methoxytryptophan.<h4>Background</h4>Sepsis, a critical organ dysfunction resulting from an aberrant host response to infection, remains a leading cause of mortality in ICU patients. Recent evidence suggests that angiotensin-converting enzyme 2 (ACE2) contributes to intestinal barrier function, the mechanism of which is yet to be explored. Additionally, alterations in intestinal microbiota and microbial metabolites could affect gut homeostasis, thus playing a potential role in modulating sepsis progression.<h4>Results</h4>ACE2 shedding weakens the integrity of the intestinal barrier in sepsis. Mice deficient in ACE2 exhibited increased intestinal permeability and higher mortality rates post-operation compared to their wild-type counterparts. Notably, ACE2 deficiency was associated with distinct alterations in gut microbiota composition and reductions in protective metabolites, such as 5-methoxytryptophan (5-MTP). Supplementing septic mice with 5-MTP ameliorated gut leak through enhanced epithelial cell proliferation and repair. The PI3K-AKT-WEE1 signaling pathway was identified as a key mediator of the beneficial effects of 5-MTP administration.<h4>Conclusion</h4>ACE2 plays a protective role in maintaining intestinal barrier function during sepsis, potentially through modulation of the gut microbiota and the production of key metabolite 5-MTP. Our study enriched the mechanisms by which ACE2 regulates gut homeostasis and shed light on further applications. Video Abstract.2025-01-01T00:00:00Z2025 May2026-05-29T03:15:30.263Z2026-05-29T03:06:14.66ZS-EPMC121237364044281610.1186/s40168-025-02128-4